Triple helix forming oligonucleotides (TFOs) offer the potential to specifically modulate expression of any gene in a sequence dependent manner. At present, TFOs can be designed to bind to certain targets in duplex DNA, forming a localized three-stranded structure. Such structures can block action of a variety of DNA binding proteins, including transcription factors. TFOs can be administered in cell culture and are taken up and transported to the cell nucleus. Thus, intervention in the expression of specific genes relevant to various disease states may soon be practical. TFOs consisting of guanosine and thymidine residues that bind to duplex DNA, forming a series of GGC and TAT base triplets, are being studied. Recently, indications are that T is relatively nonspecific in that it binds with similar affinity to AT, GC, and CG base pairs. This may significantly reduce the specificity of a given TFO, leading to undesired effects on the expression of genes unrelated to the intended target. Preliminary studies indicate the base analog pyrido-pyrimidine affords comparable binding affinity and significantly greater specificity for AT base pairs. Additional experiments designed to confirm these results and extend them to antiviral studies in culture are proposed.